Prescribing antidepressants to children and pregnant women is becoming increasingly common. However, it hasn't been clear whether these medications pose a risk to the developing brain.

In a new study, researchers provide evidence that, in young mice, the antidepressants known as selective serotonin reuptake inhibitors (SSRIs) permanently alter the brain, resulting in a greater risk of depression and anxiety in adulthood.

SSRIs seem to combat depression by affecting a molecule, called a transporter, on the surface of some brain cells. The molecule's main role is to absorb serotonin, a brain chemical that regulates mood. SSRIs probably prevent the transporter from taking in serotonin, thereby increasing the amount of free serotonin in the brain and lightening a person's disposition.

Jay Gingrich and his colleagues at Columbia University had previously shown that mice engineered to be missing a gene for the serotonin transporter show anxiety and depression once they reach adulthood. The mood problems of these knockout mice were unexpected, Gingrich says, because when SSRIs inactivate the serotonin transporter in normal, mature mice, they ease depression symptoms, as they do in people.

"We thought that maybe the reason we're having this paradoxical effect is that in knockout mice, the [transporter] gene is disabled for the animal's life span, so it's rewiring the brain early in development to make the animals more susceptible to anxiety and depression later in life," he says.

To test this theory, Gingrich's team treated litters of both normal and knockout mice with fluoxetine, an SSRI commonly known as Prozac. The time of treatment, from ages 4 days to 21 days, corresponds to the period from approximately the third trimester of pregnancy to age 8 years in people.

After the mice matured, the scientists exposed them to several stressful situations, such as mild foot shocks or new cages. Compared with normal mice that hadn't received the drug during their development, both knockouts and mice that had received fluoxetine earlier in life showed more signs of anxious and depressed behaviors. For example, these mice took significantly longer to try to avoid foot shocks and showed less interest in exploring new environments.

Gingrich and his colleagues presented the findings this week at the Neuroscience 2004 meeting in San Diego and in the Oct. 29 Science.

According to Gingrich, the research suggests that the serotonin transporter plays a pivotal role in normal brain formation. Consequently, if SSRIs block the transporter's function while the brain is still developing, they could permanently disrupt mechanisms that control mood.

"Like all good studies, this raises more questions than it answers," says David Fassler, a clinical associate professor of psychiatry at the University of Vermont in Burlington. Although the results don't immediately translate to people, he says, "I think everyone agrees that we need more research on the long-term effects of these medications on children and adolescents and on children who may have been exposed prenatally."

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